The number of patients suffereing from type II diabetes is increasing worldwide, and progress of the patient's conditions and development of the complication cause a severe prognosis, under which the circumstances the development of a novel prophylactic agent or a therapeutic agent is eagerly desired. Type II diabetes, with the background of genetic predisposition and aging suggested to be associated with the development thereof, is considered to have a significantly increased risk of the development when the life style common in developed countries, namely, the condition involving an excessive energy intake to physical activities, is imposed. Also, the metabolic disorders, which are the underlying conditions, include poor glucose utilization in the skeletal muscle and fat tissues, insulin secretion disorder from pancreatic beta cells, and insufficient control of glucose release from the liver and an agent to improve these disorders is considered to be useful for preventing and treating type II diabetes.
For the glucose utilization in the skeletal muscle and fat tissues, a drug therapy using insulin sensitizers represented by a thiazolidine derivative (e.g., pioglitazone) is considered to be effective; however, aggravated obesity, body fluid retention, increased risk of cardiac insufficiency, increased incidence of bladder cancer, and the like, have been reported, where careful assessment is hence required when using these drugs. Further, for the insulin secretion disorder, sulfonylurea drugs (e.g., glimepiride, glibenclamide, glipizide) are considered to be effective; however, hypoglycemia and/or overweight is often caused, and also poor blood glycemic control (secondary failure) may occur due to reduced therapeutic effects when used for an extended period of time, thus leaving both safety and efficacy issues to be resolved. For the postprandial hyperglycemia, α-glucosidase inhibitors (e.g., acarbose, voglibose, and miglitol), or glinide drugs (e.g., nateglinide, repaglinide, and mitiglinide) are used but have limited therapeutic effects on diabetes. For controlling the glucose release from the liver, biguanide drugs (e.g., metformin) are effective, but glycemic control becomes difficult as conditions progress and additionally, in some cases, use of the drug may be limited due to the adverse effects on the digestive tract, lactic acidosis risk, or the like. As evident from the findings of the above major agents, the existing agents do not necessarily meet the medical requirements. In particular, metformin is substantially the only agent for directly improving the liver glucose metabolism, under which circumstance it is extremely essential to develop an agent capable of improving the liver glucose metabolism by a novel mechanism of action.
Glucokinase (hereinafter described as GK) belongs to the hexokinase family and catalyzes phosphorylation of glucose incorporated in cells such as pancreatic beta cells or hepatocytes. GK in the liver and pancreatic beta cells differ from each other in terms of the sequence of N-terminal 15 amino acids due to the difference in splicing but are enzymatically identical. GK has a high affinity to glucose S0.5 of about 10 mM and is not inhibited by the product, glucose 6-phosphate. Therefore, its reaction rate sensitively responds to physiological changes of blood glucose levels. GK in pancreatic beta cells modulates glucose-dependent insulin secretion, while GK in the liver modulates the glycolytic pathway or glycogenesis, so that blood glucose levels are maintained and controlled. Therefore, GK is assumed to function as a glucose sensor to maintain homeostasis of blood glucose levels (see Non Patent Literature 1).
Genetically engineered mice and gene mutations discovered in humans support a hypothesis that GK functions as an in vivo glucose sensor. GK homozygous mice have been died of hyperglycemia immediately after birth, and heterozygous mice have been observed to have hyperglycemia and impaired glucose tolerance (see Non Patent Literature 2). In contrast, GK overexpressed mice have been confirmed to have hypoglycemia (see Non Patent Literature 3). Moreover, in human MODY2 (maturity onset diabetes of the young), in which GK gene mutation is observed, diabetes develops from his youth (see Non Patent Literature 4). These gene mutations have been confirmed to reduce GK activity. In contrast, families have been reported having gene mutations to enhance GK activity (see Non Patent Literature 5). These gene mutations have been observed to enhance affinity of GK to glucose and cause symptoms of fasting hypoglycemia associated with elevated blood insulin concentrations.
In this way, GK has been shown to function as a glucose sensor in mammals including humans.
Substances to increase GK activity (hereinafter described as GK activating substances) may improve hyperglycemia by increasing glucose metabolism and glycogenesis in the liver and glucose-responsive insulin secretion from pancreatic beta cells. In particular, the substances which increase GK activity predominantly in the liver may improve hyperglycemia by promoting the glucose metabolism in the liver in an insulin-independent manner. It can also expected that improvement of hyperglycemia leads to treatment and prevention of chronic diabetic complications such as retinopathy, nephropathy, neurosis, ischemic heart disease and arteriosclerosis and to treatment and prevention of diabetes-related diseases such as obesity, hyperlipidemia, hypertension and metabolic syndrome. Therefore, compounds to increase the function of GK are expected to be effective therapeutic agents for diabetes.
On the other hand, GK has been reported to be expressed not only in the pancreas and liver but also in the feeding center and to have an important function in the antifeeding effect by glucose (see Non Patent Literature 6). Accordingly, GK activating substances may act on the feeding center and have an antifeeding effect and can be expected not only as therapeutic agents for diabetes but also as therapeutic agents for obesity.
Incidentally, some compounds having 2-pyridone are reported as the GK activating substances but they are structurally far removed from those of the present invention (see Patent Literatures 1 and 2). Other 2-pyridone compounds having closely related structures are reported but the compounds of the present invention are not disclosed specifically (see Patent Literatures 3 and 4). The present invention differs from the report in that the report contains no description regarding the medical application and that it rather focuses on a synthetic method of 2-pyridone compounds (see Non Patent Literature 7). Further, certain acylurea compounds that may have a pseudocyclic structure have been reported as GK activating substances, but they are noncyclic compounds and differ from the compounds of the present invention (see Patent Literatures 5 and 6).